It has been previously demonstrated that cancers of neuroectodermal origin specifically express the GD2-O-acetylated ganglioside and that a therapeutic antibody targeting GD2-O-acetylated ganglioside (mAb 8B6) can be administrated and show beneficial effects without neurotoxicity, especially due to the absence of expression of this cancer antigen on healthy cells, notably on peripheral nerves.
The potent activity of the anti-OAcGD2 murine IgG3,κ mAb 8B6 has been described in ALVAREZ-RUEDA et al. (PLoS One, vol. 6(9), p:e25220, 2011). This antibody has an efficient ADCC and CDC activity in vitro, and also shows a pro-apoptotic activity (COCHONNEALU et al., Cancer Lett., vol. 333(2), p: 194-204, 2013). This antibody induces cell death by an apoptotic pathway corresponding to the inhibition of the proliferation for OAcGD2 positive tumor cells in culture via cell cycle arrest and apoptosis in vitro.
Passive immunotherapy performed with mAb 8B6 to OAcGD2 is effective in suppressing the growth of OAcGD2-expressing tumor in three animal models. It was demonstrated that lytic function of NK cells is not a requirement for the in vivo activity of mAb 8B6 (COCHONNEAU et al., above mentioned, 2013).
Now, to develop a humanized antibody the inventors have generated a human-mouse chimeric antibody, named c8B6 (IgG1, κ).
While this c8B6 antibody showed an in vivo activity comparable to that of in immuno-competent mice tumor models, a complete loss of pro-apoptotic activity compared to murine mAb 8B6 was observed in vitro. It was thus envisaged that the loss of pro-apoptotic activity of mAb c8B6 results from the loss of specific structures that differs between murine IgG3 and human IgG1.
Consequently, it was concluded that an IgG1 human chimerization can not be done for obtaining a valuable therapeutic.